Dihydrodibenzoxazepines



United rates Pattit @fificei Patented Jan. 1, 1963 This inventionrelates to new basically substituted dihydrodibenzoxazepines (and theirsalts) having valuable therapeutic properties, processes for thepreparation thereof, and new intermediates useful in such processes.

The therapeutically active compounds of this invention includedihydrodibenzoxazepines of the general formula:

wherein A is a lower alkylene radical, B is a basic saturatednitrogen-containing radical of less than twelve carbon atoms, and R andR are the same or different and represent hydrogen, halogen, lower.alkyl, lower alkoxy, trifluoromethyl, trifiuorornethylmercapto,trifluoromethoxy or N,N-dimethylsulfonamido. Among the suitable radicalsrepresented by the symbol B are: amino; (lower alkyl)amino; di(loweralkyl)amino; (hydroxy lower alkyl)arnino; di(hydroxy-lower alkyl)amino;and basic saturated 5 to 6 membered N-heterocyclic radicals of less thantwelve carbon atoms, as exemplified by piperidyl [i.e., piperidino,Z-piperidyl, 3-piperidyl and 4-piperidyl]; (lower alky1)piperidyl [e.g.,2, 3, or 4-(lower alkyl) piperidino 0r 2, 3, or 4-(N-loweralkyl)piperidyl]; di-

(lower alkyl)-piperidyl [e.g., 2,4-, 2,5-, or 3,5-di(loweralkyl)piperidino, or 2, 3, or 4-(N-lower alkyl)-2, 3, or 4- (loweralkyl)piperidyl]; (lower alkoxy)piperidyl; pyrrolidyl; (lower-alkyl)pyrrolidyl; di(lower alkyl)pyrrolidyl; (lower alkoxy)pyrrolidyl;morpholinyl [i.e., morpholine, Z-morpholinyl and 3-morpholinyl]; (loweralkyl)morpholinyl; di(lower alk-yl)rnor-pholinyl; (loweralkoxy)m'orpholinyl; thiamorpholinyl; (lower alkyl)thiamorpholinyl;di(lower alkyUthiamorpholinyl; (lower alkoxy)thia-morpholinyl;piperazyl; (lower alkyl)piperazyl (e.g., N -met-hylpiperazino); di(lower-alkyl)piperazyl; (lower alkoxy)piperazyl; (hydroxy-lower alkyl)piperazyl [e.g., N -(2-hydroxyethyl)piperazino]; (loweralkanoyloxyalkyl)piperazyl [e.g., N (2 acetoxyethyl) piperazino];(hydroxy-lower alkoxy-lower alkyl)piperazyl [e.g., N-(Z-hydroxyethoxyethyl)piperazino]; and (car bo-lower alkoxy)piperazyl[e.g., (2carbomethoxy, carboethoxy, or carbopropoxy)piperazino]. Theterms lower alkyl, lower alkoxy, and lower alltylene, as employedherein, include both straight and branched chain radicals of less thaneight carbon atoms. The particularly preferred com-pounds are thosewherein A is a lower alkylene radical of two to three carbon atoms(i.e., ethylene, trimethylene-1,3, and propylenel,2); B represents adi(lower alkyl)amino radical, an N -(lower alkyl)piperazino radical, anN -(2-hydroxyethyl)piperazino radical, or an N-(2-acetoxyethyl)piperazino radical, and R and R are hydrogen.

As to salts of the dihydrodibenzoxazepines, those coming within thepurview of this invention include the acidaddition salts, particularly,the non-toxic acid-addition salts. Acids useful for preparing theacid-addition salts, include, inter alia, inorganic acids, such as thehydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuricacid, nitric acid and phosphoric acid, and organic acids, such asoxalic, maleic, tartaric, citric, acetic and succinic acid.

The compounds of this invention are therapeutically active compoundswhich are utilizable both as atar-actic agents, and thus may be used inthe treatment of depressed psychotic states, and an antihistamines. Forthese purposes they may be administered orally or parenterally inconventional dosage forms such as tablets, capsules, in-

- jectables or the like by incorporating the appropriate dose of thecompound with carriers according to accepted pharmaceutical practice.

The compounds of this invention are prepared by the process of thisinvention which is shown in the following equation, wherein R, R, A andB are as hereinbefore defined:

application, Serial No. 90,225, filed on even. date here with. Thesestarting materials are treated with a basically substituted loweralkanoyl halide of the formula: B-ACO halide, wherein B and A are ashereinbefore defined, the reaction preferably being conducted in thepresence of a basic condensation reagent, such as sodium hydride, toyield the final products of this invention. The same compounds canalternatively be prepared in two steps, by first reacting with a halo(lower alkanoyl) halide of the formula: (halo)-ACO halide and then witha base of the formula: BH. To prepare the acid-addition salts, theresulting base is treated with the desired acid in the usual manner.

The following examples illustrate the invention (all temperatures beingin Centigrade).

EXAMPLE .1

Z-Dimethylamr'noethyl 5,1l-Dihydrodibenz [b,e] [1,4] Oxazepin-S-YlKetone (a) Preparation 0) Z-chloroethyl 5,11-dihydrodibenz [b,e] [1,4]0xazepin-5-yl ketone.-A mixture of 9.0 g. of 5,11-dihydrodibenz [b,e][1,4] oxazepine, 11.7 g. of l3-chloropropionyl chloride and 150 ml. ofdry toluene is refluxed for four hours, treated with Darco, filtered,and concentrated to dryness to leave a gummy residue weighing about 10.8 g. The gum crystallizes on drying in vacuo and afterrecrystallization from hexane melts at about 98-99".

(h) Preparation of Z-dimethylaminoethyl 5,11-dihydrodibenz [b,e] [1,4]oxazepin-S-yl ket0ne.A mixture of 10.8 g. of 2-chloroethyl5,11-dihydrodibenz [b,e] [1,4] oxazepin-S-yl ketone, 18.0 g. ofanhydrous dimethylamine and 50 ml. of toluene is heated in a sealed tubeat 98 for 24 hours. The reaction mixture is then fil= tered, thefiltrate is concentrated to dryness, and the oily residue dissolved in100 ml. of ether. The ether solution is extracted with 100 ml. of 5%aqueous hydrochloric acid, the extract made alkaline and the basereextracted with ether. After drying, the ether is removed bydistillation and the residue recrystallized three times from a verysmall amount of diisopropyl ether to give about 5.0 g. of product, M.P.about 78.5-80.0".

EXAMPLE 2 Z-Diethylaminoethyl 5,11-Dihydrdibenz [b,e] [1,4]Oxazepin-S-Yl Ketone Following the procedure of Example 1 butsubstituting an equivalent amount of diethylamine for the dimethylaminein step b, Z-diethylaminoet-hyl 5,11-dihydrodibenz [b,e] [1,4]oxazepin-S-yl ketone is obtained.

EXAMPLE 3 Z-Dimethylaminoethyl 5,11-Dihydr0dibenz [b,e] [1,4]Oxazepin-S-Yl Ketone Hydrochloride To a solution of 5.92 g. of2-dimethylaminoethyl 5,1-1- dihydrodibenz [b,e] [1,4] oxazepin-S-ylketone in 25 ml. of anhydrous ether is added 0.75 g. of hydrogenchloride in 10 ml. of anhydrous ether. The precipitated solid isfiltered, dried and recrystallized from acetonitrile-ether to giveZ-dimethylaminoethyl 5,11-dihydrodibenz [b,e] [1,4] oxazepin-S-yl ketonehydrochloride.

EXAMPLE 4 Z-Dimethylaminoethyl 3-Chl0ro-5,Z1-Dihydrodibenz [b,e] [1,4]Oxazepin-S-Yl Ketone Following the procedure of Example 3, butsubstituting an equivalent amount of 3-chloro-5,ll-dihydrodibenz [b,e][1,4] oxazepine for the 5,11-dihydrodibenz [b,e] [1,4] oxazepine in stepa, Z-dimcthylaminoethyl 3-chloro- 5,11-dihydrodibenz [b,e] [1,4]oxazepin-S-yl ketone is obtained.

EXAMPLE 5 Z-Dimethylaminoethyl 3- Trifluorom ethyl) -5,1 l-Dyhydrodibenz[b,e] [1,4] 0xazepin-5-Yl Ketone Following the procedure of Example 1,but substituting an equivalent amount of3-(trifluoromet-hyl)-5,1l-dihydrodibenz [b,e] [1,4] oxazepine for the5,11-dihydrodi benz [b,e] [1,4] oxazepine for the 5,11-dihydrodibenz[b,e] [1,4] oxazepine in step a, Z-dimethylaminoethyl3-(trifluoromethyl)-5,11-dihydrodibenz [b,e] [1,4] oxa- Zepin-S-ylketone is obtained.

Similarly, by substituting an equivalent amount of3-(trifluoromethoxy)-5,11-dihydrodibenz [b,e] [1,4] oxazepine,3-(trifluoromethylmercapto -5, l l-di'hydrodibenz [b,e] [1,4] oxazepineor 3-(N,N-dimethylaminosulfonyl)- 5,11-dih-ydrodibenz [b,e] [1,4]oxazepine for the 5,11- dihydrodibenz [b,e] [1,4] oxazcpiue in step a,Example 1, Z-dimethylaminoethyl 3-(trifluoromethoxy) -5,1l-dihydrodibenz [b,e] [1,4] ox-azepin-S-yl ketone, Z-dimethylaminoethyl3 (trifluoromethylmercapto)-5,1l-dihydrodibenz [b,e] [1,4] oxazepin-S-yland Z-dimethylaminoethyl 3-(N,N-dimethylaminosulfonyl) -5,1l-dihydrodibenz [b,e] [1,4] oxazepin-5-yl are prepared, respectively.

EXAMPLE 6 2-D imethylaminoethyl 7-M ethyl-5 ,1 1 -Dihydr0dibenz [b,e][1,4] Oxazepin-5-Yl Ketone Following the procedure of Example 1, butsubstituting an equivalent amount of 7-methyl-5,1l-dihydrodibenz [b,e][1,4] oxazepine for the 5,11-dihydrodibenz [b,e] [1,4] toxazepine instep a, Z-dimethylarninoethyl 7-methyl- 5,11-dihydrodibenz [b,e] [1,4]oxazepin-S-yl ketone is obtained.

EXAMPLE 7 2 Dimethylaminoeflzyl 3,7-Dichlor0-5,1J-Dihydrodibenz [1,4]Oxazepirz-S-Yl Ketone Following the procedure of Example 1, butsubstituting an equivalent amount of 3,7-dic-hloro-5,1l-dihydrodibenz[b,e] [1,4] oxazepine for the 5,11-dihydrodibenz [b,e] [1,4] oxazepinein step a, Z-dimethylarninoethyl 3,7- dichloro-5,1l-dihydrodibenz [b,e][1,4] oxazepin-S-yl ketone is obtained.

4 EXAMPLE 8 Dimethylaminomethyl 5,11-Dihydrodibenz [b,e] [1,4]Oxazepin-5-Yl Ketone Following the procedure of Example 1, butsubstituting an equivalent amount of chloroacetyl chloride for thefl-chloropropionyl chloride in step a, dimethylaminomethyl5,11-dihydrodibenz [b,e] [1,4] oxazepin-S-yl ketone is obtained.

EXAMPLE 9 2- (N -Methy lpiperazino) Ethyl 5 ,1 1 -D ihydrodibenz [b, [14 Oxazepin-S-Yl Ketone Following the procedure of Example 1, butsubstituting an equivalent amount of N-methylpiperazine for thedimethylamine in step b, 2-(N -methylpiperazino)ethyl5,11- dihydrodibenz[b,e] [1,4] oxazepin-S-yl ketone is ob tained.

Similarly, by substituting an equivalent amount of N- (Z-hydroxyethylpiperazine, N- Z-acetoxyethyl) piperazinc, orN-(Z-hydroxyethoxyethyl)piperazine for the dimethylamine in step b ofExample 1, 2-[N -(2-hydroxyethyl)piperazino]ethyl 5,1l-dihydrodibenz[b,e] [1,4] oxazepin-S-yl ketone, 2-[N -(Z-acetoxyethyl)piperazino]ethyl 5,11-dihydrodibenz [b,e] [1,4] oxazepin-S-yl ketone, and 2- [N2-hydroxyethoxyethyl piperazino] ethyl 5,11- dih-y-drodibenz [b,e] [1,4]oxazepin-S-yl ketone are obtained respectively.

This invention may be variously otherwise embodied Within the scope ofthe appended claims.

What is claimed is:

1. A compound selected from the group consisting of bases of the formulawherein A is lower alkylene, B is selected from the group consisting ofamino, (lower alkyl)amino, di(lower a1- kyl)amino, (hydroxy-loweralkyl)amino, di(hydroxylower alkyl)amino, piperidyl, (loweralkyl).piperidyl, di(lower alkyl)piperidyl, (lower alkoxy)piperidyl,pyrrolidyl, (lower alkyl)pyrrolidyl, di(lower a1kyl)pyrrolidyl, (loweralkoxy)pyrrolidyl, morpholinyl, (lower alkyl)morpholinyl, di(loweralkyl)morpholinyl, (lower alkoxy)morpholinyl, thiamorpholinyl, (loweralkyl)thiamorpholinyl, di(lower alkyl)thiamorpholinyl, (loweralkoxy)thiamorpholinyl, piperazyl, (lower alkyl)piperazyl, di(loweralkyl)piperazyl, (hydroxy-lower a1kyl)piperazyl, (loweralkanoyloxyalkyl)piperazyl, (hydroxy-lower alkoxy-lower alkyl)piperazyl,and (carbo-lower alkoxy) piperazyl and R and R are each selected fromthe group consisting of hydrogen, halogen, lower alkyl, lower alkoxy,trifluoromethyl, trifluoromethylmercapto, trifluoromethoxy andN,N-dimethylsulfonamido and non-toxic acidaddition salts thereof.

2. Di(lower alkyl)amino(lower alkyl) 5,11-dihydrodibenz [b,e] [1,4]oxazepin-S-yl ketone.

3. A non-toxic acid-addition salt of the compound of claim 2.

4. 2 dimethylaminoethyl 5,11-dihydrodibenz [b,e] [1,4] oxazepin-S-ylketone.

5. A compound of the formula [I O A (halide) C Hz 0 wherein A is loweralkylene and R and R are each se- 5 6 lected from the group consistingof hydrogen, halogen, 7. Z-chloroethyl 5,11-dihydrodibenz [-b,e] [1,4]oxazelower alkyl, lower alkoxy, trifluoromethyl, trifluoromethpin-S-ylketone.

ylmercapto, trifiuoromethoxy and N,N-dimethylsulfon- References Cited inthe file of this patent amido.

6. Chloroflower alkyl) 5,11-dihydrodibenz [b,e] [1,4] 5 UNITED STATESPATENTS Q a epi11 5-y1 ketone Hafiiger et a1 .Tan. 12,

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BASES OF THE FORMULA